Molecular mechanisms of tumor necrosis factor‐induced cytotoxicity

Beyaert, Rudi; Fiers, Walter

doi:10.1016/0014-5793(94)80163-0

Cited by 230 publications

(153 citation statements)

References 78 publications

(44 reference statements)

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“…We were interested in determining if cyclin G might have a similar role. It is well established that TNF-a is a potent inducer of apoptosis in many cell types (Ashkenazi and Dixit, 1998;Beyaert and Fiers, 1994), and can initiate apoptosis in a p53-independent manner.…”

Section: Resultsmentioning

confidence: 99%

A role of cyclin G in the process of apoptosis

1999

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Cyclin G was previously identi®ed as a target gene of the p53 tumor suppresser protein, and levels of cyclin G are increased after induction of p53 by DNA damage. However, the function of cyclin G has not been established. To determine the e ect of increased expression of cyclin G, retroviruses encoding cyclin G were constructed and used to infect three di erent murine cell lines. Cyclin G protein levels induced by the retroviruses were within the range seen after DNA damage induction of p53. In each case we observed that such over-expression of cyclin G augments the apoptotic process. TNF-a induction of apoptosis is increased by expression of cyclin G in NIH3T3 ®broblasts which express p53, as well as in 10.1 ®broblasts which contain no p53 allele. Additionally, we observed that while cyclin G expression is markedly reduced upon aggregate formation in embryonic carcinoma P19 cells, retrovirus-mediated over-expression of cyclin G enhances apoptotic cell death in aggregated P19 cells, and increases the extent of apoptosis caused by retinoic acid or serum starvation of these cells. These data demonstrate that cyclin G plays a facilitating role in modulating apoptosis induced by di erent stimuli. Moreover, we have discovered that cyclin G expression is rapidly induced in P19 cells after exposure to Bone Morphogenic Protein-4 (BMP-4), suggesting that cyclin G may mediate apoptotic signals generated by BMP-4.

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Section: Resultsmentioning

confidence: 99%

A role of cyclin G in the process of apoptosis

1999

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“…Oxidative damage has been implicated in some forms of TNF-mediated cytotoxicity [4]. Between 1% and 5% of the oxygen consumed by mitochondria is converted to damaging free radicals [10] and, at least in TNF-induced death of L929 cels, the lack of mitochondrial function abolish TNF toxicity [11].…”

Section: Introductionmentioning

confidence: 99%

mtDNA‐depleted U937 cells are sensitive to TNF and Fas‐mediated cytototxicity

et al. 1995

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It has been proposed that TNF cytotoxicity is mediated by reactive oxygen intermediates generated by uncoupling of mitochondrial respiration. We have compared sensitive U937 cells and derived cell lines depleted of mtDNA for their ability to undergo TNF-and Fas-induced apoptosis. Cells lacking around 98% of mtDNA were still sensitive to TNF-induced apoptosis. U937 cells devoid of mtDNA (U937-p °) were resistant to TNF, but this was due to the loss of its 55 kDa receptor. U937-p ° cells were also resistant to docosahexaenoic acid, which causes U937 cell death by lipid peroxidation. These cells were sensitive to anti-Fas toxicity. The results indicate that TNF and Fasinduced toxicity occurs by a mechanism mostly independent of mitochondrial free radical generation.The mechanism by which Fas ligation triggers apoptosis, as well as a general biochemical mechanism for the apoptosis process itself, are unknown [5]. Some reports have suggested, however, the lack of implication of oxidative damage in cytotoxicity induced with anti-Fas, using antioxidants [14,15] or anaerobic conditions [16].In the present work, we have studied the effect of TNF and anti-Fas on U937 cells and in derived cell lines depleted of mtDNA by prolonged exposure to low doses of ethidium bromide. Results indicate that impairment of mitochondrial function and lipid peroxidation do not play a key role in the apoptosis induced by both molecules in human myeloid cells.

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“…It seemed that FAK could stimulate PKB levels through a pathway not involving PtdIns3K. These results suggest that FAK can affect the sensitivity of SMMC-7721 cells to TNF-a/Chx-induced apoptosis in a biphasic manner by regulating PKB levels.Keywords: focal adhesion kinase; protein kinase B; SMMC-7721 cells; tumor necrosis factor-a; cycloheximide; apoptosis.TNF-a is a potent cytokine that can elicit a wide range of cellular effects, including cell proliferation, differentiation, and apoptosis depending on the various cell types [1]. However, most cell lines are resistant to TNF-a-induced apoptosis and undergo apoptosis only when they are treated with TNF-a in the presence of other agents such as cycloheximide (Chx), actinomycin D or vanadate [1 -5].…”

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confidence: 99%

Focal adhesion kinase affects the sensitivity of human hepatocellular carcinoma cell line SMMC‐7721 to tumor necrosis factor‐α/cycloheximide‐induced apoptosis by regulating protein kinase B levels

Fang

Wang

Jin

et al. 2001

European Journal of Biochemistry

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Most cell lines are resistant to tumor necrosis factor-a (TNF-a) cytotoxicity and require cotreatment of TNF-a with cycloheximide (Chx) to undergo apoptosis. Recently, the serine/threonine protein kinase, protein kinase B has been demonstrated to protect cells from apoptosis induced by TNF-a. In this study, we have shown that the human hepatocellular carcinoma cell line, SMMC-7721, was insensitive to TNF-a cytotoxicity and underwent apoptosis quickly in the presence of TNF-a and Chx. PKB levels decreased during TNF-a/Chx-induced apoptosis. No significant change in PKB levels was found in the presence of TNF-a or Chx alone. It seemed that the level of PKB closely correlated with apoptosis. The protein level of focal adhesion kinase (FAK) was reduced by 66% by transfecting FAK antisense cDNA recombinant vector into SMMC-7721 cells. We determined the apoptosis-induced effect of TNF-a/Chx on the FAK antisense cDNA transfectant cells. The results indicated that the percentage of apoptotic cells was enhanced at lower doses of TNF-a (10, 20 or 50 U : mL 21 ) and decreased at a higher dose of TNF-a (1000 U : mL 21 ) in the transfected cells as compared to the control. Correspondingly, in the FAK antisense cDNA transfectant cells treated with lower doses of TNF-a in presence of 10 mg : mL 21 Chx, the PKB level was lower, but in the FAK antisense cDNA transfectants treated with higher doses of TNF-a in presence of 10 mg : mL 21 Chx, the PKB level was higher. In response to TNF-a alone, FAK antisense cDNA transfectants showed a decrease in the level of PKB. However, in the case of TNF-a cotreated with wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PtdIns3K), the FAK antisense cDNA transfectants produced significantly less amounts of PKB than the control. It seemed that FAK could stimulate PKB levels through a pathway not involving PtdIns3K. These results suggest that FAK can affect the sensitivity of SMMC-7721 cells to TNF-a/Chx-induced apoptosis in a biphasic manner by regulating PKB levels.Keywords: focal adhesion kinase; protein kinase B; SMMC-7721 cells; tumor necrosis factor-a; cycloheximide; apoptosis.TNF-a is a potent cytokine that can elicit a wide range of cellular effects, including cell proliferation, differentiation, and apoptosis depending on the various cell types [1]. However, most cell lines are resistant to TNF-a-induced apoptosis and undergo apoptosis only when they are treated with TNF-a in the presence of other agents such as cycloheximide (Chx), actinomycin D or vanadate [1 -5]. How these cells achieve resistance to TNF-a cytoxicity is still unclear. Recently, increasing evidence points to a role for PKB in preventing TNF-a-induced apoptosis. PKB is a serine/threonine protein kinase that can be phosphorylated by the action of TNF-a [2]. The phosphorylated PKB can phosphorylate and inactivate its downstream targets such as Bcl2/Bcl-X(L)-antagonist, causing cell death (BAD) [6] as well as caspase-9 [7]. BAD is a proapoptotic protein [8,9] capable of forming heterodimers with the antia...

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Molecular mechanisms of tumor necrosis factor‐induced cytotoxicity

Cited by 230 publications

References 78 publications

A role of cyclin G in the process of apoptosis

A role of cyclin G in the process of apoptosis

mtDNA‐depleted U937 cells are sensitive to TNF and Fas‐mediated cytototxicity

Focal adhesion kinase affects the sensitivity of human hepatocellular carcinoma cell line SMMC‐7721 to tumor necrosis factor‐α/cycloheximide‐induced apoptosis by regulating protein kinase B levels

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